Plasma lipids: harbingers of AD?

A
panel of plasma lipids could represent a new diagnostic tool for identifying
patients likely to develop Alzheimer's disease before symptoms appear,
according to new clinical findings from a team of U.S. researchers.1
Although the lipid panel could help enrich clinical trials of AD therapeutics
for likely responders, validation studies will need to confirm its specificity
for AD over other forms of dementia.

Diagnosis
of AD and its precursor, mild cognitive impairment (MCI), currently involves
detecting changes in biomarkers that often occur together with or after the
onset of neurocognitive symptoms. In addition, measuring levels of the key
biomarkers-b-amyloid (Ab) and its peptides,
and microtubule-associated protein-t (MAPT; tau; FTDP-17)-requires invasive procedures
such as lumbar puncture or costly and time-consuming methods such as PET
imaging or functional MRI scans.

Simple
blood tests to detect AD noninvasively before the onset of symptoms have become
the Holy Grail for diagnosing the disease. Several studies have tried to
correlate the progression of MCI to AD with blood levels of small molecules, Ab peptides, tau or
other proteins.2-4 However, none has identified blood markers that
could predict which cognitively normal individuals are at risk of developing
AD.

To
bridge this diagnostic gap, a team headed by Mark Mapstone and Howard Federoff
conducted a 5-year clinical study to look for plasma markers in individuals age
70 or older with no cognitive impairment that could predict which of them would
develop AD or amnestic MCI (aMCI)-the memory-related form of MCI that most
often progresses to AD.

The
team enrolled 525 participants with no history of major neurological,
psychiatric or blood disorders. Blood samples were withdrawn and cognitive
tests performed at the start of the study and every year thereafter.

Of
the 74 patients who were identified with symptoms of AD or aMCI during
the study, 46 already had symptoms at the start of the study but had never been
diagnosed with aMCI or AD. The other 28 became symptomatic during the study's
course. The average time for the latter group-labeled 'converters'-to show
symptoms was 2.1 years.

From the original 525 participants, another 73
age-matched individuals with no cognitive impairment were selected as normal
controls.

The
team performed lipidomic and metabolomic analyses of the plasma samples and
found a panel of 10 lipids whose levels were significantly lower in the
normal-functioning converters before they developed symptoms than in the control
group. The lipid levels remained low after the converters showed signs of
cognitive impairment and were comparable to levels in the 46 patients with AD
or aMCI.

The
lipid panel included eight phosphatidylcholines and two acylcarnitines, all of
which are components of cell membranes in multiple cell types. The team
proposed that the observed changes in plasma lipids might reflect a breakdown
of neuronal cell membranes that precedes the onset of subtle cognitive changes.
Their hypothesis was based on multiple studies that identified associations
between AD and low phospholipid levels in plasma and the CNS.5-10

Finally, the team developed a mathematical model that
used the 10 lipid markers to predict which initially unaffected individuals
would develop aMCI or AD with 90% sensitivity and 90% specificity.

According to the paper's authors, the findings suggest
that the panel of lipid markers could be used to identify cognitively normal
individuals who would convert to a diagnosis of aMCI or AD within two or three
years.

The study was published in Nature Medicine.

Lipid
AD-vances

"The
study potentially opens a new door in biomarker development for Alzheimer's
disease," said Stephen Salloway. "Having a plasma profile that is
associated with the disease and that can predict its progression would be a
major advance."

According
to Norman Foster, director of the Center for Alzheimer's Care, Imaging and
Research, senior investigator at The Brain Institute and a professor of
neurology at The University of Utah, "The ability
to predict the onset of clinical symptoms in two to three years would
definitely advance the field by allowing the benefits of treatments to be
identified over a very short time."

Xiaoming Guan added that the markers should be tested in a
younger population to see whether the changes in these lipids can be detected
even earlier. Guan is senior director of
the Neurodegeneration Discovery Performance Unit at GlaxoSmithKline plc's R&D center in
Shanghai.

According to Richard Pither, CEO of Cytox Ltd., the ability to detect
which presymptomatic patients are likely to develop AD could be particularly
beneficial for companies developing disease-modifying therapies.

"This
panel of markers could help get those compounds into the right patients,"
he said.

Cytox
develops diagnostic tests for identifying patients at risk of AD or other forms
of dementia.

However,
Howard Fillit said that in addition to validating the findings in a larger
patient population, the team needs to establish that the markers are specific
for AD.

Because
the team did not use cerebrospinal fluid (CSF) markers or PET imaging scans to
diagnose MCI and AD in the converters, it is not certain that they actually had
the diseases, he said.

Indeed,
Salloway and Foster said that it would be useful to examine whether the changes
in plasma lipid levels coincide with changes in CSF or PET imaging markers for
AD.

Foster
added that the findings should be replicated in other populations, using Ab and/or tau markers
to show whether the lipids in the panel are altered when there is evidence of
AD pathology.

Determining
whether the lipid markers correlate with CSF and imaging markers for AD would
also help rule out-or rule in-Lewy body dementia and other forms of non-AD-related
dementia in the converters, Pither said. "Looking at these lipids in
patients who have other forms of dementia could also help determine whether the
markers are AD specific or not."

Fillit
added that because most people aged 70 and older have comorbidities such as
atherosclerosis, vascular abnormalities in the brain or other cardiovascular
conditions, "the altered lipid levels might just be markers for cognitive
impairment due to vascular inflammation, not Alzheimer's disease."

Mapstone
agreed that the lipid markers need to be validated in a larger and more
demographically diverse population than was used in the study. But he countered
Fillit's concerns about comorbidities by pointing out that the same risk
factors for MCI unrelated to AD were probably present in the controls as well
as the converters.

"We
haven't looked at those comorbidities in our cohort, but I think that if we
did, we wouldn't see major differences in them between the converters and
controls-just as we saw no differences in the frequency of apolipoprotein E e4 between the two groups," he said. "But
we did see differences in the lipid levels."

Last
week, the Alzheimer's Association issued a statement
noting that the findings were preliminary and required replication and
validation in larger, more diverse populations. The organization declined SciBX's
request for further comment.

Road map for
markers

The
team's immediate next step is to validate the lipid markers in a larger,
retrospective study using banked plasma samples-such as those from the
Alzheimer's Disease Neuroimaging Initiative (ADNI), Mapstone told SciBX. Once
the samples are in hand, he expects to be able to complete the validation
within a few months.

In
the meantime, the researchers are continuing to follow the 21 converters who
developed aMCI to see whether they go on to develop full AD.

In
addition, Mapstone told SciBX that although the lipid panel is not ready
for use as a routine AD screening test, it could be used to assist patient
selection in clinical trials in AD.

"Our
approach could enrich the trial population with a larger fraction of potential
converters than other markers such as apolipoprotein E e4, which carries a
30% risk of AD," he said.

"Potential
converters would be randomized between the placebo and treatment arms. We would
expect the converters in the placebo group to progress to MCI or AD, thus
providing validation of the markers. We would also monitor the individuals
identified as nonconverters to confirm that they did not develop MCI or AD,
which would further validate the markers," he said.

To
monitor treatment responses and track disease progression, the trial would use
CSF and PET imaging markers because they are considered the gold standards, he
added.

Mapstone
said that a forthcoming paper by the team will report data from transcriptome
analysis of plasma from its study cohort and integrate those findings with the
lipid data reported in Nature Medicine.

Ultimately,
the team aims to use a systems biology approach-incorporating lipidomic,
transcriptomic and genomic data from the study cohort-to identify cognitively
normal individuals who will develop MCI and AD.

Other
efforts to identify markers for early detection of AD and for monitoring
disease progression include the ADNI. The study has enrolled more than 1,000
participants, including patients with AD or MCI, individuals at risk of
developing AD and controls who have no memory problems.11

Mapstone
said that Georgetown and the University
of Rochester have filed a patent application covering the Nature
Medicine findings. The technology will be available for licensing once the
validation study on banked samples has been completed.

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